This application is a 371 of PCT/FR98/02671 filed Dec. 9, 1998.
The present invention concerns novel echinocandin derivatives their method of preparation and their application as anti-fungal agents.
The invention has as its object, the compounds of formula (I), in any of the possible isomer forms as well as their compounds,: 
in which
either R1 and R2 identical or different from one another, represent a hydrogen atom, a hydroxyl radical, an alkyl radical containing up to 8 linear branched or cyclic carbon atoms, optionally interrupted by an oxygen atom optionally substituted by a halogen atom, an OH radical, an 
radical, a and b identical or different from one another,
representing a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, a and b optionally able with the nitrogen atom to form a heterocycle optionally containing one or several additional heteroatoms,
or else R1 forms a double bond with the endocyclic carbon atom
carrying the radical 
or else R2 represents an XRa radical, X representing an oxygen atom or an NH or N-alkyl radical containing up to 8 carbon atoms and Ra represents a hydrogen atom, a linear, branched or cyclic alkyl radical containing up to 8 atoms of carbon optionally substituted by one or several halogen atoms, by one or several OH, CO2H CO2alc radicals,
by an 
radical, axe2x80x2 and bxe2x80x2 representing a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, axe2x80x2 and bxe2x80x2 able to form a heterocycle optionally containing one or several additional heteroatoms and/or by a heterocycle containing one or several heteroatoms or R2 represents a radical 
in which d, e, f, and g represent a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, f and g able moreover to represent an acyl radical containing up to 8 carbon atoms, e and f able equally to form a ring optionally containing one or several heteroatoms,
R3 represents a hydrogen atom, a methyl or hydroxyl radical
R4 represents a hydrogen atom or a hydroxyl radical R representing a linear or branched or cyclic chain containing up to 30 carbon atoms, optionally containing one or several heteroatoms, one or several heterocycles or a linear, branched or cyclic acyl radical containing up to 30 carbon atoms optionally containing one or several heteroatoms and/or one or several heterocycles,
T represents a hydrogen atom, a methyl radical, a CH2CONH2, CH2Cxe2x89xa1N radical, a (CH2)NH2 or (CH2)2Nalc+Xxe2x88x92 radical, X being a halogen atom and alc an alkyl radical containing up to 8 carbon atoms,
Y represents a hydrogen atom, a hydroxyl radical or a halogen atom or an OSO3H radical or one of the salts of this radical,
W represents a hydrogen atom or an OH radical,
Z represents a hydrogen atom or a methyl radical, as well as the addition salts with the acids of the products of formula (I).
Amongst the addition salts with the acids, those formed with mineral acids, such as hydrochloric, hydrobromic, sulphuric or phosphoric acids or the organic acids like formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic, such as sulphonic methane or ethane, arylsulphonic acids like the benzene or paratoluenesulphonic acids can be cited.
In the definition of the substituents,
the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, or cyclohexyl radical,
the halogen is preferably fluorine or chlorine or bromine,
the aryl radical is preferably the radical phenyl,
the heterocyclic radical is preferably the pyrrolyle, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, quinuclidinyl, oxazoyl, isoxazoyl, morpholinyl, indolyl, imidozoyl, benzimidazoyl, triazoyle, thiazolyl, azetidinyl, aziridinyl radical.
as a salt of the SO3H radical, sodium, potassium salts or even the salts of amines can in particular be cited.
Amongst the preferred compounds of the invention:
the compounds of formula (I), in which T represents a hydrogen atom,
the compounds of formula (I), in which Y represents a hydrogen atom,
the compounds of formula (I), in which W represents a hydrogen atom,
the compounds of formula (I), in which Z represents a methyl radical,
the compounds of formula (I), in which R3 represents a methyl radical,
the compounds of formula (I), in which R4 represents a hydroxyl radical
the compounds of formula (I), in which R represents a radical can be especially cited. 
and more particularly those in which R represents a chain 
or those in which R represents a chain 
the compounds of formula (I) in which R1 forms with the endocyclic carbon atom carrying the NR1R2 radical, a double bond, and notably those in which R2 represents the radical
O(CH2)nNYxe2x80x22
in which n represents an integer between 1 and 8 and very particularly those in which n represents the number 2 and Yxe2x80x2 represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, and those in which R represents a radical 
The invention has equally particularly as its object the compounds of formula (I) in which R2 represents a radical
xe2x80x94(CH2)pN(Yxe2x80x3)2
in which Yxe2x80x3 represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms and p represents an integer varying from 1 to 8 and especially the compounds in which p represents the number 2.
The invention has very particularly as its object, compounds in which R1 represents a hydrogen atom.
Amongst the preferred compounds of the invention, the products of examples 8, 9, 11, 13 and 14 can be cited.
The compounds of formula (I) present significant anti-fungal properties; they are active notably on Candida albicans and other Candida like Candida glabrata, krusei, tropicalis, pseudotropicalis, parapsilosis and Aspergillus fumigatus, Aspergillus flavus, Cryptococcus neoformans. 
The compounds of formula (I) can be used as medicines in man or animal, to fight against notably digestive urinary, vaginal or cutaneous candidoses, cryptococcoses, for example neuromenengeal, pulmonary or cutaneous cryptococcoses, bronchopulmonary and pulmonary aspergilloses and invasive aspergilloses of immunocompromise.
The compounds of the invention can be equally used in the prevention of mycosic ailments in people with congenital or acquired immune compromise.
The compounds of the invention are not limited to a pharmaceutical usage, they can be equally used as fungicides in domains other than pharmaceutical.
The invention thus has as its object as anti-fungal compounds, the compounds of formula (I) as well as their addition salts with the acids.
The invention equally has as its object the compounds of formula (I), as medicines.
The invention has very particularly as its object pharmaceutical compositions containing at least one compound of formula (I) or one of its addition salts with pharmaceutically acceptable acids as active ingredient.
These compounds can be administered by oral, rectal, parenteral route or by local route by topical application on the skin and the mucous membranes, but the preferred route is the oral route.
They can be solid or liquid and be presented in pharmaceutical forms currently used in human medicine, like for example, simple or sugar coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared following usual methods. The active ingredient(s) can be incorporated into excipients usually used in these pharmaceutical compositions, like talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous mediums, fatty bodies of animal or vegetable origin, paraffin derivatives, glycol, various diluting, dissolving or emulsifying agents, preservatives.
These compositions can equally be presented in the form of a powder intended to be dissolved extemporarily in an appropriate medium, for example apyrogenic sterile water.
The administered dose varies according to the ailment treated, the subject concerned, the route of administration and the considered product. It can, for example, consist of between 50 and 300 mg per day by oral route, in adults for the products of examples 8, 9, 11, 13 and 14.
The invention equally has as its object a method of preparation of formula (I) compounds, characterised in that a formula (II) compound is submitted: 
in which R, R3, R4, T, W, Y and Z retain their prior meaning, with the action of an amine or an amine derivative likely to introduce
the radical 
in which R1 and R2 retain their prior meaning and if desired the action of a reduction agent
and/or a functionalisation agent of the amine,
and/or an acid to form the salt of the obtained product,
and/or a separation agent of the different isomers obtained,
and thus obtains the sought formula (I) compound 
in which R1, R2, T, W, Y, R and Z retain their prior meaning in all of its possible isomer forms as well as their compounds and/or in the forms of salts with the acids.
The formula (II) compounds used as initial compounds of the process of the invention are novel products and are themselves an object of the present invention, their preparation given in the experiment section can be schematised as follows: 
Isi-(CH3)3 or any other Lewis acid can be used.
A detailed example of the preparation of the compound of formula (II) is given in the experiment section, and the invention has more particularly as its object as novel chemical product 1-[4-oxo-N2-(12-methyl-1-oxotetradecyl) L-ornithine]4-(4-hydroxyphenyl)-L-threonine}-5-L-serine-echinocandin B.
The product (IV) corresponding to the initial product of preparation 1 is a known product described and claimed in the European patent 438813.
The following examples illustrate the invention without at the same time limiting it.
The invention equally has as its object a preparation process characterised in that a formula (III) compound is submitted 
in which the different substituents retain their prior meaning with the action of an agent capable of replacing NH2 with NHR, R retaining its prior meaning to obtain the formula (IV) compound 
in which the different substituents retain their prior meaning and are submitted to the action of silyl trimethyl iodide to obtain the compound of formula (II).
The compounds of formula (III) used as initial products are novel products and are themselves an object of the present invention. An example of preparation of the formula (III) compound is given hereafter in the experiment section.
The invention has more particularly as its object the deoxymulundocandin nucleus, compound of formula (III) the preparation of which is given hereafter in the experiment section.
The formula (IV) compounds as described above, with the exception of mulundocandin and deoxymulundocandin are novel products and are in themselves an object of the present invention.
The invention has more particularly as its object the compounds of formula (IV) whose preparation is given in the experiment section.